The present invention generally relates to a minimally invasive method for administering focused energy such as adaptive microwave phased array hyperthermia for treating ductal and glandular carcinomas and intraductal hyperplasia as well as benign lesions such as fibroadenomas and cysts in compressed breast tissue. In addition, the method according to the invention may be used to treat healthy tissue containing undetected microscopic pathologically altered cells of high-water content to prevent the occurrence of or the recurrence of cancerous, pre-cancerous or benign breast lesions.
In order to treat primary breast cancer with hyperthermia, it is necessary to heat large volumes of tissue such as a quadrant or more of the breast. It is well known that approximately 90% of all breast cancers originate within the lactiferous ductal tissues (milk ducts) with much of the remaining cancers originating in the glandular tissue lobules (milk sacks) (Harris et al., The New England Journal of Medicine, Vol. 327, pp. 390-398, 1992). Breast carcinomas often involve large regions of the breast for which current conservative treatments have a significant risk of local failure. Schnitt et al., Cancer, Vol. 74 (6) pp. 1746-1751, 1994. With early-stage breast cancer, known as T1 (0-2 cm), T2 (2-5 cm) cancers, the entire breast is at risk and often is treated with breast-conserving surgery combined with full-breast irradiation to destroy any possible microscopic (not visible to the human eye without the aid of a microscope or mammography) cancer cells in the breast tissue (Winchester et al., CA-A Cancer Journal for Clinicians, Vol. 42, No. 3, pp. 134-162, 1992). The successful treatment of invasive ductal carcinomas with an extensive intraductal component (EIC) where the carcinomas have spread throughout the ducts is particularly difficult, since large portions of the breast must be treated. Over 800,000 breast needle biopsies of suspicious lesions are performed annually in the United States with approximately 180,000 cases of cancer detected, the rest being nonmalignant such as fibroadenomas and cysts.
The use of heat to treat breast carcinomas can be effective in a number of ways, and in most cases the heat treatment must be capable of reaching, simultaneously, widely separated areas within the breast. Heating large volumes of the breast can destroy many or all of the microscopic carcinoma cells in the breast, and reduce or prevent the recurrence of cancerxe2x80x94the same approach is used in radiation therapy where the entire breast is irradiated with x-rays to kill all the microscopic cancer cells. Heating the tumor and killing a large percentage or all of the tumor cells prior to lumpectomy may reduce the possibility of inadvertently seeding viable cancer cells during the lumpectomy procedure, thus reducing local recurrences of the breast. Sometimes, the affected breast contains two or more tumor masses distributed within the breast, known as multi-focal cancer, and again the heating field must reach widely separated regions of the breast. Locally advanced breast carcinomas (known as T3) (Smart et al., A Cancer Journal for Clinicians, Vol. 47, pp. 134-139, 1997) can be 5 cm or more in size and are often treated with mastectomy. Pre-operative hyperthermia treatment of locally advanced breast cancer may shrink the tumor sufficiently to allow a surgical lumpectomy procedure to be performedxe2x80x94similar to the way pre-operative chemotherapy is currently used. Pre-operative hyperthermia treatment of locally advanced breast cancer may destroy the tumor completely, eliminating the need of any surgery.
It is well known that microwave energy can preferentially heat high-water content tissues such as breast tumors and cysts, compared to the heating that occurs in low-water content tissue such as fatty breast tissue. Many clinical studies have established that hyperthermia (elevated temperature) induced by electromagnetic energy absorption in the microwave band, significantly enhances the effect of radiation therapy in the treatment of malignant tumors in the human body (Valdagni, et al., International Journal of Radiation Oncology Biology Physics, Vol. 28, pp. 163-169, 1993; Overgaard et al., International Journal of Hyperthermia, Vol. 12, No. 1, pp. 3-20, 1996; Vernon et al., International Journal of Radiation Oncology Biology Physics, Vol. 35, pp. 731-744, 1996; van der Zee et al, Proceedings of the 7th International Congress on Hyperthermic Oncology, Rome, Italy, April 9-13, Vol. 11, pp. 215-217, 1996). Radio-resistant cells such as S-phase cells can be killed directly by elevated temperature (Hall, Radiobiology for the Radiologist, 4th Edition, JB Lippincott Company, Philadelphia, pp. 262-263, 1994; Perez and Brady, Principles and Practice of Radiation Oncology, Second Edition, JB Lippincott Company, Philadelphia, pp. 396-397, 1994). Hyperthermia treatments with microwave radiating devices are usually administered in several treatment sessions, in which the malignant tumor is heated to about 430xc2x0 C. for about 60 minutes. It is known that the amount of time to kill tumor cells decreases by a factor of two for each degree increase in temperature above about 43xc2x0 C. (Sapareto, et al., International Journal of Radiation Oncology Biology Physics, Vol. 10, pp. 787-800, 1984). Thus, a 60-minute treatment at 43xc2x0 C. can be reduced to only about 15 minutes at 45xc2x0 C., which is often referred to as an equivalent dose (t43xc2x0 C. equivalent minutes). During treatments with noninvasive microwave applicators, it has proven difficult to heat semi-deep tumors adequately while preventing surrounding superficial healthy tissues from incurring pain or damage due to undesired hot spots. The specific absorption rate (SAR) in tissue is a common parameter used to characterize the heating of tissue. The SAR is proportional to the rise in temperature over a given time intenval times the specific heat of the tissue and for microwave energy the SAR is also proportional to the electric field squared times the tissue electrical conductivity. The units of absolute SAR are watts per kilogram.
Incoherent-array or non-adaptive phased array hyperthermia treatment systems typically are restricted in their use for heating deep tissue, because they tend to overheat intervening superficial tissues, which can cause pain and/or burning. The first published report describing a non-adaptive phased array for deep tissue hyperthermia was a theoretical study (von Hippel, et al., Massachusetts Institute of Technology, Laboratory for Insulation Research, Technical Report 13, AD-769 843, pp. 16-19, 1973). U.S. Pat. No. 3,895,639 to Rodler describes two-channel and four-channel non-adaptive phased away hyperthermia circuits. Recent developments in hyperthermia systems effectively targets the delivery of heat to deep tissue using adaptive phased array technology originally developed for microwave radar systems (Skohuk, Introduction to Radar Systems, Second Edition, McGraw-Hill Book Company, 1980 pp. 332-333; Compton, Adaptive Antennas, Concepts and Performance, Prentice Hall, New Jersey, p. 1 1988; Fenn, IEEE Transactions on Antennas and Propagation, Vol. 38, number 2, pp. 173-185, 1990; U.S. Pat. Nos. 5,251,645; 5,441,532; 5,540,737; 5,810,888).
Bassen et al., Radio Science, Vol. 12, No. 6(5), November-December 1977, pp. 15-25, shows that an electric-field probe can be used to measure the electric-field pattern in tissue, and in particular, shows several examples in which the measured electric-field has a focal peak in the central tissue. This paper also discusses a concept for real-time measurements of the electric-field in living specimens. However, Bassen et al. did not develop the concept of measuring an electric field using real-time with an electric-probe to adaptively focus a phased array.
An adaptive phased array hyperthermia system uses E-field feedback measurements to focus its microwave energy on deep tissue while simultaneously nullifying any energy that might overheat surrounding healthy body tissue. Pre-clinical studies indicate that adaptive microwave phased arrays have the potential for delivering deep heat while sparing superficial tissues from excessive temperatures in deep torso (Fenn, et al., International Journal of Hyperthermia, Vol. 10, No. 2, March-April, pp. 189-208, 1994; Fenn et al., The Journal of Oncology Management, Vol. 7, number 2, pp. 22-29, 1998) and in breast (Fenn, Proceedings of the Surgical Applications of Energy Sources Conference, 1996; Fenn et al., International Journal of Hyperthermia, Vol. 15, No. 1, pp. 45-61, 1999; Gavrilov et al., International Journal of Hyperthermia, Vol. 15, No. 6, pp. 495-507, 1999).
The most difficult aspect of implementing hyperthermia in deep breast tissues, with microwave energy, is producing sufficient heating at a predetermined depth while protecting the skin from burns. Noninvasive multiple applicator adaptive microwave phased arrays with invasive and noninvasive electric field probes can be used for producing an adaptively focused beam at the tumor position with adaptive nulls formed in healthy tissues as described in U.S. Pat. Nos. 5,251,645, 5,441,532, 5,540,737, and 5,810,888, all of which are incorporated herein by reference. Ideally, a focused microwave radiation beam is concentrated at the tumor with minimal energy delivered to surrounding healthy tissue. To control the microwave power during treatment, a temperature-sensing feedback probe (Samaras et al., Proceedings of the 2nd International Symposium, Essen, Germany, June 2-4, 1977, Urban and Schwarzenberg, Baltimore, 1978, pp. 131-133) is inserted into the tumor, however, it is often difficult to accurately place the probe in the tumor. An additional difficulty occurs in delivering hyperthermia to carcinoma spread throughout the ductal or glandular tissues of the breast, because of a lack of a well defined target position for the temperature-sensing feedback probe. In other situations, it is desirable simply to avoid inserting probes (either temperature or E-field) into the breast tissue in order to reduce the risk of infection or spreading the cancer cells when the probe passes through the tumorregion or when it is undesirable for the probe to penetrate the lesion such as a cyst.
The standard of medical care for treating benign cysts that have been detected varies from doing noting to draining the cysts. The medically accepted position of not treating the cysts exists because the only known method of removing cysts involves invasive surgery. The alternative to surgically cutting and removing a cyst is draining the cyst. Draining the cyst is achieved by piercing the cyst and removing the liquid inside the cyst. While this method may temporarily relieve the pain associated with the cyst, the cyst may grow back if the draining procedure failed to remove the entire cyst. Therefore, there is a need for a non-invasive removal of these benign cysts.
The above problems are solved by the method for heating cancerous or benign conditions of the breast according to the invention which comprises the steps of inserting an E-field probe sensor in the breast, monitoring temperatures of the skin surface, orienting two microwave applicators on opposite sides of the breast, setting the initial microwave power and phase delivered to each microwave applicator in order to focus the field at the inserted E-field sensor, adjusting the microwave power to be delivered to the breast based on the monitored skin temperatures, and monitoring the microwave energy dose delivered to the breast being treated and completing the treatment when a desired total microwave energy dose has been delivered by the microwave applicators.
Moreover, the method according to the invention has application in situations such as when there is no well-defined position to place the temperature feedback sensor, or when it is desirable to avoid inserting a temperature probe into the breast tissue. Only a single sly minimally invasive E-field sensor is required in the preferred method according to the invention. Thus, in the case of advanced breast cancer (e.g., a tumor 5-8 cm), the inventive method can destroy a significant portion of the breast cancer cells and shrink the tumor or lesion (i.e., thermal downsizing to e.g., 2-3 cm) thereby replacing a surgical mastectomy with a surgical lumpectomy. In the alternative, the entire advanced breast cancer lesion can be destroyed (i.e., a thermal mastectomy) and no surgery may be required. In early-stage breast cancer or for small breast lesions, the inventive method may destroy all of the breast cancer cells or benign lesions with heat (i.e., a thermal lumpectomy) thereby avoiding a surgical lumpectomy. In addition, the method ran be used to enhance radiation therapy or for targeted dog delivery with thermosensitive liposomes as described in U.S. Pat. No. 5,810,888 and/or targeted gene therapy delivery.
The method according to the invention destroys the cancerous cells while sparing the normal glandular, ductal, connective, and fatty tissue of the breast. Thus, a thermal lumpectomy according to the invention avoids damage to such healthy tissue and is a breast conservation technique.
The breast skin surface can be measured by attaching temperature probe sensors to the skin surface of the breast. Alternatively, the skin surface (as well as internal breast tissue) temperature can be monitored by other external means, including infrared, laser ultrasound, electrical impedance tomography magnetic resonance imaging, and radiometry techniques as known in the art
Alternatively, a temperature probe could be inserted at an appropriate depth in the breast tissue to monitor the temperature thereof. As discussed below, insertion of a temperature probe is not a preferred embodiment.
The method according to the invention can be achieved with or without breast compression. In a preferred method, a patient""s breast would be compressed between 3 and 8 cm with compression plates. The microwave applicators would be oriented on exterior sides of the compression plates (ie., the sides of the compression plates away from the breast).
As described below, recent clinical measured data for compressed, living breast tissue supports applicants"" inventive step of monitoring the microwave energy dose delivered to the breast being treated and completing the treatment based on the total microwave energy dose that has been received. That is, conventional temperature feedback measurements of tumor thermal dose can be replaced with the total microwave energy delivered to the phased array microwave applicators. Accordingly, with the instant invention, instead of temperature feedback measurements which require the insertion of a temperature feedback probe into the breast and its inherent problems, microwave energy dose is used as feedback to determine the required length of treatment In this application the term xe2x80x9cmicrowave energy dosexe2x80x9d (in Joules or watt-seconds) is similar to the dose used in radiation therapy, namely the radiation absorbed dose (Rad) which is a unit of absorbed dose of radiation defined as deposition of 100 ergs of energy per gram of tissue.
Thus, the instant method for selectively heating cancerous conditions of the breast avoids the risk of spreading cancer cells since the temperature probe is not inserted into the treated area (tumor bed) of the breast. The elimination of an inserted temperature probe reduces the risk of infection to a patient as a result of the inserted probe. Likewise, the microwave field applied to a tumor would not be subjected to scattering or other disturbance caused by a temperature probe, especially a metallic probe. In addition, the time and costs associated with inserting the temperature probe are saved.
The inventive method may also be used to treat healthy breast tissue or undetected high-water content microscopic precancerous or pre-benign cells in seemingly healthy breast tissue to prevent the occurrence of or recurrence of cancerous conditions of the breast. The cancerous conditions that can be prevented include invasive ductal and lobular carcinoma and pre-cancerous conditions of the breast including ductal carcinoma in-situ, lobular carcinoma in-situ, and intraductal hyperplasia and benign lesions (such as cysts and fibroadenomas). Thus, the method according to the invention would be able to destroy microscopic precancerous or pre-benign cells before they are detected. This would be an early treatment that could prevent cancer before it is detected. In the case of healthy tissue, the breast tissue would be irradiated with microwave energy focused at high-water content microscopic cells that are known to form lesions.
In a preferred method, the patient lies prone with the breast pendulant through a hole in the treatment table and the treated breast is compressed with flat plastic compression plates which immobilizes the breast tissue, reduces blood flow, and reduces the penetration depth required for the microwave radiation. The breast compression plates are made of a microwave transparent plastic material, and contain one or more apertures to allow imaging of breast tissues and placement of a minimally invasive E-field feedback probe at the desired focal depth. The placement of an E-field feedback probe may be achieved with an ultrasound transducer or other type of image guidance.
Two microwave air-cooled waveguide applicators (such as described by Cheung et al., Radio Science, Vol. 12, No. 6(S), November-December 1977, pp. 81-85.) are positioned on opposite sides of the compression plates. A phased away can be achieved with a multiple number of applicators greater than or equal to two. In a preferred embodiments coherent 915 MHz microwave power is delivered to the two waveguide applicators, at a predetermined power level, while phase shifters in each channel are adjusted to maximize and focus the microwave energy at the E-field probe sensor. The air flow from individual fans surrounding the breast or from fans mounted in the applicator waveguides may be adjusted. The airflow cooling the waveguide applicators would go through the applicators. The air for cooling the waveguide applicators may be refrigerated, air-conditioned or room temperature. Water-cooled waveguide applicators may be substituted for air-cooled applicators, as one of ordinary skill in the art would recognize.
During the hyperthermia treatment, the microwave power level delivered to each of the applicators may be adjusted either manually or automatically to control the skin temperatures to avoid high temperatures that could cause skin burns or blisters. In addition, the amount of breast compression by compression plates, if used, is adjusted as necessary during treatment to provide patient comfort. Each time the breast compression is adjusted or the breast repositioned, the microwave-energy, phased array is refocused so that the E-field probe sensor receives maximum power. The total microwave energy, since the start of the treatment, delivered to the microwave applicators is monitored during the treatment. The treatment is completed when a desired amount of total microwave energy is delivered to the microwave applicators, which indicates that the breast lesion cells are significantly (i.e., thermal downsizing) or completely destroyed (i.e., thermal lumpectomy).
In order to determine the effectiveness of the treatment, the breast tissue may be imaged and examined with mammography means including x-ray, ultrasound, and magnetic resonance imaging before and after the microwave total energy dose is administered, as well as with pathological results from needle biopsy of the breast tissues.
In an alternate embodiment of the invention, the single invasive E-field sensor is replaced with two E-field sensors positioned on opposite sides of the breast skin surface and the array is phase focused by minimizing (nulling) the combined power received by the two sensors, providing a completely noninvasive treatment. Algorithms are used in conjunction with the feedback signals sensed by the E-field skin sensors to null areas on the outside thereby focussing the applied energy on an internal site.
Such a totally non-invasive hyperthermia treatment where E-field probes and temperature sensors monitor the breast skin surface would provide an effective method of destroying benign cysts and the pain associated therewith. Thus, applicants"" inventive method is envisioned as treating or destroying detected benign cysts.
While the preferred embodiment is described with reference to adaptive microwave phased array technology, Applicants"" method may be achieved by focussing energy, in general, to heat and ablate an area of tissue. The focused energy may include electromagnetic waves ultrasound waves or waves at radio frequency. That is, applicants"" inventive method includes any energy that can be focused to heat and ablate an area of tissue.
In yet another embodiment of the invention, the boundary of an area of tissue to be treated in a body (e.g., breast) is calculated, an E-field probe may be inserted in the body or at least two E-field sensors are positioned on the outside of the body; and energy is applied through applicators to the area to be treated. In this embodiment, the focus of the energy would change so that the focus scans the area to be treated. That is, there is no longer a fixed focus spot as the relative phase of the applied energy would be adjusted so that the focus moves inside the area to be treated thereby obtaining a geometric shape of heating.
A fixed focus spot is determined through the appropriate algorithm. Then, for example, the relative phase of the applicators to obtain this fixed focus spot is adjusted 30xc2x0 one way and then 30xc2x0 the other way to xe2x80x9cscanxe2x80x9d a larger heated/treated area. Depending on the size of the area to be treated the scan may focus between 180xc2x0 and 90xc2x0 or 60xc2x0 or 120xc2x0.